Is metformin a wonder drug? Some scientists think so due to its many positive health impacts.

 
History

Metformin comes from a traditional herbal medicine called Galega officinalis, which was used for a variety of purposes in medieval Europe. Guanidine and related compounds were later isolated from the plant. While it has been known to reduce blood glucose since the early 1900s, guanidine was not widely used due to its toxic effects. In the 1950s, French scientist Jean Sterne conducted human experiments on metformin that resulted in increased interest. Metformin was approved for diabetes in the U.K. in 1958 and in Canada in 1972 but was not the preferred medication. Long-term studies were completed in the 1990s that increased its use and approval for Type 2 diabetes in the U.S. in 1994. It’s available in both immediate and extended-release formulas. In 2013, metformin was added to the World Health Organization’s List of Essential Medicines (see this review).

Safety

Metformin has a long history of safe use. It has been prescribed for 70+ years to treat Type 2 diabetes. Metformin is available to take orally and has a very good safety profile. The most common side effects involve gastrointestinal issues such as nausea, diarrhea, and loss of appetite. Gradually increasing the dose and taking this medication with food can help reduce symptoms, which usually decrease over time.

Some individuals develop a deficiency in vitamin B12 or folic acid, which may require supplements. Lactic acidosis is a rare but serious risk, especially for individuals with kidney impairment. Only about 4% of participants in metformin clinical trials in the U.S. were unable to continue due to side effects. Serious adverse events are infrequent and generally limited to lactic acidosis, which occurs only in persons with renal or hepatic insufficiency or other contraindications. Metformin is not recommended for individuals with liver or kidney problems, or those receiving treatment for heart failure.

Expanding uses of metformin

Metformin is known to have effects on health beyond glucose regulation. Studies on type 2 diabetic individuals taking metformin have shown reduced risks of heart disease, cancer, and neurodegenerative diseases. Metformin has also been used in the treatment of polycystic ovary disease and COVID-19. This page provides a brief overview of some of its possible uses. While it shows promise to treat or prevent a variety of health conditions, more randomized clinical trials are needed to fully understand when and how it should be used.

Metformin is best known for its ability to lower blood sugar. It’s the most widely prescribed medication for the treatment of type 2 diabetes, with over 150 million people worldwide taking it daily.

Metformin was first used to treat diabetes in the 1950s. It’s considered a safe drug. Metformin treatment has not been associated with hypoglycemia (low blood sugar) unless used with other glucose-lowering medicines such as sulfonylureas or insulin.

How metformin lowers blood sugar

Metformin inhibits glucose production in the liver. It increases the use of glucose by the skeletal muscles and fat tissues by increasing insulin sensitivity in these tissues. Despite metformin being used for many years, uncertainty remains about its exact molecular action in the body.

Weight loss

Metformin is associated with weight loss when used to treat diabetes and thus differs from most other antidiabetic medications that are associated with weight stability or gain. For example, during the Diabetes Prevention Program clinical trial, individuals receiving metformin for Type 2 diabetes had an average weight loss of 2.1 kg (4.6 lbs).

The University of Minnesota led the COVID-OUT clinical trial, which finished enrolling participants in 2022. It was a large, rigorous study to understand whether common, inexpensive medicines (including metformin) prevent severe COVID-19 infection and Long COVID symptoms.

The main findings, which were published in the New England Journal of Medicine, included that metformin reduced emergency room visits, hospitalization, or death from COVID-19 infection by 42%. Metformin reduced serious outcomes by over 50% when taken immediately after symptoms.

There was also a 41% decrease in the incidence of Long COVID when metformin was taken shortly after COVID-19 infection. When taken within four days of symptoms, metformin reduced Long COVID by 63%. Further analyses indicated that metformin had anti-viral effects. Metformin decreased the amount of COVID-19 virus (SARS-CoV-2) by 3.6 fold.

For more information on the use of metformin to treat COVID-19, see our page COVID-19 page.

Polycystic ovary syndrome (PCOS) is a common hormonal imbalance that affects 6-13% of women of reproductive age. It occurs when the ovaries produce high amounts of androgens (like testosterone), causing irregular periods, infertility, acne, excess body hair growth, obesity, cysts on the ovaries, and other symptoms.

The high androgens are influenced by insulin resistance, which often causes high glucose levels and even diabetes. PCOS also increases the risk of developing high blood pressure, heart disease, endometrial cancer, sleep apnea, and depression or anxiety.

Treatment of PCOS depends on the symptoms, individual medical history, and whether pregnancy is desired. Several medications have been used to treat PCOS, with metformin as a key drug. It’s used off-label as a first-line treatment for excess body weight, glucose, and lipid profiles. A 2023 meta-analysis concluded that “Metformin should be considered an efficacious adjunct to lifestyle interventions in adults with PCOS, especially for those with a higher BMI (body mass index), to improve weight loss, insulin resistance, and lipids.”

Metformin works by acting on the underlying insulin resistance by improving insulin sensitivity and reducing glucose production. There’s also evidence that it reduces high androgen levels.

Metformin is also an important tool to address irregular cycles and infertility. It’s used as an alternative to oral contraceptives to improve menstrual cycles and ovulation. Studies have shown that metformin reduces weight gain during pregnancy and decreases the risk of preterm delivery.

Individuals with type 2 diabetes are at an increased risk of cancer. In the last two decades, observational studies and meta-analyses have reported a reduction in the incidence of cancer and improved outcomes with the use of metformin for diabetics. Some studies also reported a lower cancer risk in non-diabetic individuals receiving metformin. This has led to great interest in evaluating the potential for metformin to be used for cancer prevention and treatment. See details in the “Deep Dive” section.

As an antidiabetic medicine, metformin has been shown to decrease the formation of glucose in the liver, enhance insulin sensitivity in muscle and fat tissue, and increase glucose uptake in the gut.

A recent meta-analysis reported that metformin was associated with a decreased risk of various types of cancer in observational studies. For example, metformin treatment for type 2 diabetes in people with breast or colorectal cancer improved survival outcomes and prognosis. Metformin also worked well in conjunction with chemotherapy and immunotherapy for these cancers. Metformin has also been studied in relation to cancer of the stomach, liver, lung, ovaries, pancreas, and prostate (see this review).

However, not all results have been favorable. An analysis of 27 randomized controlled trials of individuals with obesity and/or diabetes found no difference in the incidence of cancer for those taking metformin. A 2022 randomized clinical trial reported that in patients with high-risk operable breast cancer without diabetes, metformin did not significantly improve invasive disease–free survival.

The protective role of metformin appears to be dependent on the subtype of cancer (especially for breast cancer), the hormone levels, and the glucose level. The differences found between studies could also be due to differences in the methods used, including different experimental designs. Some studies have small sample sizes, short follow-up duration, and other factors that limit their generalizability. Challenges also lie in the difference in metformin’s impact on different forms of cancer and whether the patient has diabetes or not.

With results expected from ongoing clinical trials involving metformin in the coming years, we’ll know much more about the impacts of metformin for treatment and prevention of cancer.

Scientists do not yet know precisely how metformin affects cancer cells. Potential anticancer actions of metformin include the following (for details see this review):

• Inhibition of mitochondrial respiratory chain complexes, including modulating the AMPK/mTOR pathway and inhibiting cytokines. This may lead to anticancer effects, including reduced protein and lipid synthesis, slower cancer spread, activation of autophagy (cellular breakdown and recycling), and inhibition of inflammatory responses.
• Effect on cell proliferation markers and reduced production of ROS (reactive oxygen species), oxidative stress, and DNA damage.
• Promotion of an effective immune response against tumor suppression.
• Reversal of aerobic glycolysis that is common in tumor cells, characterized by an increase in fatty acid degradation and anaerobic glycolysis.
• Other potential anticancer properties of metformin include the regulation of micro RNAs and enzymes involved in epigenetic changes.

There’s great interest in metformin’s ability to protect brain health. Metformin can affect neurons in some areas of the brain by activating AMPK (AMP-activated protein kinase) which regulates energy, metabolism, and mitochondrial function. Administration of metformin has been found to reduce neuronal damage and promote the formation of new nerve cells. Dysregulated insulin in the brain is related to aging and neurological diseases like Alzheimer’s and Parkinson’s diseases. Thus, metformin’s ability to regulate insulin may also be important for brain health.

Many studies have been conducted on metformin and neurological disease, but there are conflicting results. More research is required to understand when it may be most appropriately used. A summary of likely uses of metformin is provided here:

• Alzheimer’s disease – Some studies have reported reduced incidence of the disease in type 2 diabetics with metformin alone or with other medications. Yet, a long-term trial found that metformin was associated with a higher risk of Alzheimer’s. More research in diabetic and non-diabetic patients on metformin therapy is needed to clarify these findings.
• Parkinson’s disease – Metformin may provide neuroprotection during treatment with other drugs that cause side effects.
• Multiple sclerosis – Metformin can reduce inflammation, and by activating AMPK, it may be able to repair damaged neurons caused by multiple sclerosis.
• Epilepsy—Metformin may be used to treat seizures in the early stages of the disease to prevent seizure progression. In late-stage seizures, metformin may be combined with other seizure medications to reduce adverse effects while maintaining anti-seizure effects.
• Depression – Research on depression in individuals treated with metformin for type 2 diabetes has shown some promise, but it’s unclear whether it’s helpful in people without diabetes.
• Stroke – An initial study found that metformin treatment for type 2 diabetes reduced the risk of stroke by 50%. More recent meta-analyses reported protective outcomes on mortality and ischemic stroke severity. More clinical research is needed to determine the impact on non-diabetic individuals.

The potential positive impact of metformin on diverse disease processes like diabetes, heart disease, and obesity has led to the question of whether it might slow down aging. Research has more recently focused on metformin’s ability to increase lifespan or “healthspan” (the period free from chronic diseases).

Metformin increases insulin sensitivity. Interestingly, calorie restriction — one of the most effective methods to increase lifespan — has similar mechanisms. As discussed above for specific disease processes, metformin’s impact on aging may occur via the activation of AMPK, which lowers glucose production and stimulates mitochondrial biogenesis. This also leads to a reduction in reactive oxygen species (ROS), reduced inflammation, and reduced accumulation of cells that do not divide (senescent cells). In mice, oral metformin also altered the microbiome to increase bacteria that produce short-chain fatty acids.

While preclinical studies have shown promising results of metformin’s effects on aging and disease processes, clinical studies have had inconsistent outcomes. In fact, the MASTERS trial on strength training reported that metformin had a negative effect on the benefits of physical activity. This effect could be due to a ceiling on muscle mitochondrial function imposed by the drug.

In a review of human studies of eight promising anti-aging therapies, Guarente and colleagues reported that metformin is at the forefront of this research. Much more research on aging and metformin is needed, especially randomized controlled clinical trials. However, there are potential positive impacts of metformin on aging and diabetes, heart failure, and infectious disease. Ongoing trials will help to clarify its impacts on cognitive decline, cancer, and inflammatory diseases/gut microbiome.